三级淋巴结构在肝细胞癌中的作用与临床意义：从预后评估到免疫治疗靶点

Role and clinical significance of tertiary lymphoid structures in hepatocellular carcinoma: from prognostic assessment to immunotherapeutic targets

摘要:

肝细胞癌（HCC）是全球发病率和病死率均较高的恶性肿瘤，其肿瘤免疫微环境复杂，导致免疫治疗总体应答率仍然有限。近年来研究发现，在慢性炎症或肿瘤微环境中异位形成的三级淋巴结构（TLS）在HCC免疫调控中发挥重要作用。大量研究表明，TLS的存在、密度、成熟度及空间分布与HCC患者较好的生存预后、较低的复发风险以及更佳的免疫检查点抑制剂治疗响应密切相关。部分抗肿瘤治疗（如放疗、肝动脉灌注化疗等）还可诱导TLS形成或促进其成熟，从而改善肿瘤免疫微环境并增强抗肿瘤免疫应答。本文综述TLS的结构组成与形成机制，总结其在HCC预后评估和免疫治疗预测中的潜在价值，并重点讨论诱导或靶向TLS的治疗策略及其临床转化前景，以期为HCC精准免疫治疗提供新的研究思路。

Abstract:

Hepatocellular carcinoma (HCC) is one of the most prevalent primary liver malignancies worldwide and is associated with high mortality. The complex tumor immune microenvironment limits the overall efficacy of current immunotherapies. Recent studies have identified tertiary lymphoid structures (TLS), ectopic lymphoid aggregates formed in chronic inflammatory or tumor tissues, as key regulators of anti-tumor immunity in HCC. Accumulating evidence indicates that the presence, density, maturation status, and spatial distribution of TLS are closely associated with improved survival outcomes, reduced recurrence risk, and enhanced responsiveness to immune checkpoint inhibitors. Moreover, several anti-tumor treatments, including radiotherapy and hepatic arterial infusion chemotherapy, can induce TLS formation or promote their maturation, thereby reshaping the tumor immune microenvironment and strengthening anti-tumor immune responses. This review summarizes the structural characteristics and formation mechanisms of TLS and discusses their prognostic and predictive value in HCC. In addition, potential therapeutic strategies aimed at inducing or targeting TLS and their prospects for clinical translation are highlighted, providing new insights for precision immunotherapy in HCC.